SGLT2 inhibitor ertugliflozin decreases elevated intracellular sodium, and improves energetics and contractile function in diabetic cardiomyopathy.

BACKGROUND

Elevated myocardial intracellular sodium ([Na]) was shown to decrease mitochondrial calcium ([Ca]) via mitochondrial sodium/calcium exchanger (NCX), resulting in decreased mitochondrial ATP synthesis. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) ertugliflozin (ERTU) improved energetic deficit and contractile dysfunction in a mouse model of high fat, high sucrose (HFHS) diet-induced diabetic cardiomyopathy (DCMP). As SGLT2is were shown to lower [Na] in isolated cardiomyocytes, we hypothesized that energetic improvement in DCMP is at least partially mediated by a decrease in abnormally elevated myocardial [Na].

METHODS

Forty-two eight-week-old male C57BL/6J mice were fed a control or HFHS diet for six months. In the last month, a subgroup of HFHS-fed mice was treated with ERTU. At the end of the study, left ventricular contractile function and energetics were measured simultaneously in isolated beating hearts by P NMR (Nuclear Magnetic Resonance) spectroscopy. A subset of untreated HFHS hearts was perfused with vehicle vs. CGP 37157, an NCX inhibitor. Myocardial [Na] was measured by Na NMR spectroscopy.

RESULTS

HFHS hearts showed diastolic dysfunction, decreased contractile reserve, and impaired energetics as reflected by decreased phosphocreatine (PCr) and PCr/ATP ratio. Myocardial [Na] was elevated > 2-fold in HFHS (vs. control diet). ERTU reversed the impairments in HFHS hearts to levels similar to or better than control diet and decreased myocardial [Na] to control levels. CGP 37157 normalized the PCr/ATP ratio in HFHS hearts.

CONCLUSIONS

Elevated myocardial [Na] contributes to mitochondrial and contractile dysfunction in DCMP. Targeting myocardial [Na] and/or NCX may be an effective strategy in DCMP and other forms of heart disease associated with elevated myocardial [Na].